B cell homeostasis and autoantibody responses are tuned by a novel function interaction between Ezrin and Myo18A

Cytoskeletal proteins play key roles in modulating B cell activation and antibody responses. We reported that B cell-specific deletion of the unconventional myosin family protein Myo18A (Myo18A BKO), leads to expansion of mature B cells and plasma cells, and elevated serum immunoglobulins. Myo18A BKO mice develop stronger and persistent antigen-specific response to flu virus, and develops splenomegaly and autoantibodies, demonstrating that Myo18A enforces B cell homeostasis, and restricts both pathogen-specific and self-reactivity. Myosin18A physically and spatially interacts with the membrane-cytoskeletal linker protein Ezrin. To investigate the functional consequences of Myo18A and Ezrin interaction, we generated double knockout mice with simultaneous B cell-specific deletion of Myo18A and Ezrin. Loss of Ezrin in Myo18A BKO B cells corrected the number of mature splenic B cells and differentiation to plasma cells. Accordingly, the double knockout mice had significantly reduced antibody-secreting cells, serum IgM and autoantibody levels compared to Myo18A BKO. Mechanistically, the antigen-induced dephosphorylation of Ezrin at the C-terminal regulatory T567 site was reduced in Myo18A BKO B cells. These data indicate that enhanced Ezrin function in Myo18A BKO mice supports B cell hyperresponsiveness in the context of Myo18A deficiency. Taken together, our data reveal a novel functional interaction between Myo18A and Ezrin that tunes B cell immunity and autoimmunity.